Synthesis of steroid phosphates



SYNTHESIS or STEROID PHOSPHATES John M. Chemerda, Metuchen, and Roger J.Tull, Plainfield, NJ., and James F. Fisher, State College, Pa.,assignors to Merck 8: Co., Inc., Rahway, N.J., a corporalion of-NewJersey No Drawing. Filed Jan. 26, 1959, Ser. No. 788,707

' a 6 Claims. (Cl. 260-39145) This invention relates to processes forproducing steroid phosphates having anti-inflammatory activity, and moreparticularly to processes for producing 21-phosphate tertiaryloweralkylamine salts of ZI-hydroxy steroids of the pregnane series.

According to the present invention a 21-halo compound ora 21-lowerhydrocarbon sulfonate corresponding to and the therapeutically activenuclear substituted derivatives thereof. In the above formulas R isselected from the group consisting of p-hydroxyl n and oxo (0:), and R Rand R are lower alkyl radicals. Therapeutically-active nuclearsubstituted derivatives refers to compounds which conform to either ofthe above formulas except for the presence of one or more substituentgroups not indicated in the formulas, and which have anti-inflammatoryactivity. Among the substituent groups which may be present areZea-methyl,

a assasrs fig Patented June 7, 1960 The steroid phosphate tertiary aminesalts described in the preceding paragraph are water-soluble, stablecrystalline compounds. Unlike the steroid phosphate free acids and theamorphous alkali metal salts, the tertiary amine salts are easilycharacterized. These tertiary amine salts are valuable because of theirhigh degree of anti-inflammatory activity and low incidence of sidereactions. As a result of their water solubility and absence ofirritation to the eye, these salts are superior to previously knownproducts as anti-inflammatory active ingredients in ophthalmicsolutions. They are also superior in ointments for topical application.The amine salts are also useful as intermediates in the preparation ofthe corresponding steroid dihydrogen phosphates and alkali metal saltsin pure form..

Among the therapeutically active 2l-phosphate tertiary lower alkyl aminesalts which can be prepared by the process of this invention areprednisolone 21-phosphate triethylamine salt, prednisolone 2l-phosphatetrimethylamine salt, prednisone Ill-phosphate triethylamine salt,hydrocortisone ZI-phosphate triethylamine salt, cortisone ZI-phosphatetriethylamine salt, 9ot-fluoro-prednisolone 2l-phosphate triethylaminesalt, 9a-fluoro-l6ix-methylprednisolone 21-phosphate triethylamine salt,

and other tri-lower alkyl amine salts, such as trimethylamine salts,triisopropylamine salts, tributylamine salts, and triisoamylamine salts,corresponding to the above triethylamine salts.

Besides the therapeutically active steroid ZI-phosp'hate tertiaryloweralkyl amine salts above described, other steroid 2l-phosphate tertiarylower alkyl amine salts which, are useful as intermediates in themanufacture of therapeutically active compounds can also be prepared.These intermediates include compounds having a saturated A-ring, e.g.,11,3,17,21-trihydroxy-3,20-pregnanedione 21-phosphate triethylaminesalt, l1fi,17oc,Z1-tri hydroXy-l6B-methyl-3,ZO-pregnanedione2l-phosphate triethylamine salt, and 9a-fluoro-11B,17a,21-trihydroxy-3,ZO-pregnanedione'21-phosphate triethylamine salt, which are convertibleto the corresponding therapeutically active 4-pregnene and1,4-pregnadiene series compounds by bromination at the 4 or 2 and 4positions followedby dehydrobromination.

The steroid starting material is a 2l-halo compound, in which thehalogen has an atomic weight of at least 35, i.e., a 2l-iodo-,21-bromo-, or 21-chloro compound, or a 21-lower hydrocarbon sulfonate inwhich the hydrocarbon sulfonate radical has from one to about 10 carbonatoms, e.g. a ZI-methanesulfonate or a 21-p-toluenesulfonate,corresponding to the desired product. The starting materials for makingthe preferred therapeutically active tertiary amine phosphates arecompounds having a general formula of the group consisting of atomicweight of at least 35 and lower hydrocarbon.

1 15,17tx-dihydroxy-2 1-iodo-4-pregnene-3,20-dione, 2l-bromo-l1B,17a-dihydroxy-4-pregnene-3,20-dione,2l-chloro-1lfi,l7a-dihydroxy-4-pregnene-3,ZO-dione, Il1p,l7u,21-dihydroxy-4 pregnene-3,20-dione ZI-methanesulfonate,l1,8,l7m,21-trihydroxy-4-pregnene3,ZO-dione 21 p toluenesulfonate, 17a-hydroxy-2 l-iodo-4-pregnene-3 ,11,20-trione, 11,8, 17zx-dlhYClIOXY-Zl-iOdO-l ,4-pregnadiene-3,20-dione, 2l-chloro-l1fi,17a-dihydroxy-1,4-pregnadiene-3 ,ZO-dione, llp,l7a,21-trihydroxy-1,4pregnadiene 3,20 dione 21- methanesulfonate,11B,'17a,2l-trihydroxy-1,4-pregnadiene-3,2O dione 21 ptoluenesulfonate,1 7 u-hydroxy-2 l-iodo-1,4-pregnadi'ene-3 ,l 1,20-trione,9afluoro-1lB,17m-dihydroxy-21-iodo-4 pregnene 3,20-

dione, 9a-fluoro-l7ot-hydroxy-21-iodo-4-pregnene 3,11,20 trione, V9u-fluoro-11e,17a-dihydroxy-21-iodo 1,4 pregnadi'ene- 3,20-dione,9a-fluoro-17a-hydroxy-2Liodo-lA-pregnadiene 3,11,20-

trione, H 9a-fiuoro l1B,166,l7a-trihydroxy-21-i0do 1,4-pregnadi-'-ene-3,20-dione, 11p,17a-dihydroxy-2l-iodo-2a-methyl-4-pregnene 3,20-dione, 1l/S',l7a-dihydroxy-21-iodo-l6a-methyl-4-pregnene 3,20- dione, Y17a-hydroxy-21-iodo-16u-methy1 4 pregnene 3,11,20-

trione, a 11,8,17a-dihydroxy-16a-rnethy1-2-1-iodo L4 pregnadiene-3,20-dione, '17a-hydr'oxy-2l-iodo-16u-methyl-l,4-pregnadiene-3,l1,20-

trione, 9a-fluoro-11,8,17a-dihydroxy-2l-iodo 16a methyl 1,4-

pregnadiene-3,20-'dione,

-1 15,17a-dihydroxy-2l-iodo-3 ,20-pregnanedione,--11,8,l7u-dihydroxy-21-iodo-16a-methyl-3,20 re nancdione, V I and9a-fluoro-1l p,17a-dihydroxy-2l-iodo-l6a methyl-3, ZO-pregnanedidne.Other starting steroid "materials will also-be evident.

. Phosphoric acid'and a tertiary lower alkylamine are the other reagentsin the process of this invention. The phosphoric acid reagent" may be ofcommercial concentration, e.g. 85% or 100%, or of somewhat lowerconcentration.

The amine reagent is a tertiary lower alkyl amine such astrimethylamine, triethylamine, tributylarnine, dieth'yl isopropylamine,methyl ethyl isopropylamine, triisoaniylamine, andthe'like. The generalformula of the amine reagent is R R R N, where R R and R are lower alkylradicals as'previously indicated.

The reaction is carried out in ail-organic solvent, preferably one inwhich the steroid phosphate tertiary amine salt product is insoluble andthe other reaction products and reagents are soluble. This makes it easyto recover the product by conventional means. Acetonitrile has beenfound to be an excellent solvent fulfilling these qualifications. Othersolvents which may be used include the lower aliphatic alcohols such asmethanol and tertiary butyl alcohol. I

Both the phosphoric acid and the amine reagent are present in excessbased on the quantity of'steroid. This excess may range from slight tosubstantial. For example, the amount of phosphoric acid may beas much asten times stoichiometric quantity. The mole ratio of amineto-phosphoric' acid is preferably aboutZ-zl, but may be varied'as-longas an alkaline reaction medium is'maintained. By alkaline is meant areaction medium which is alkaline to conventional indicators whendiluted with water. Since both amine and-phosphoric acid are present,the reaction is in elfect between the steroid starting material and anamine phosphate salt. In fact, the amine can be neutralized withphosphoric acid prior to contact with the steroid starting material, andthe resulting salt, which in the preferred embodiment is the diaminephosphate, reacted with the steroid reagent.

A small amount of silver phosphate may be present in the reactionmedium, although it is not'essential. Silver phosphate appears tocatalyze the reaction.

The reaction temperature is not critical, although, in general, elevatedtemperatures are preferred. The .reaction proceeds readily at refluxtemperature. The reaction time likewise is not critical and may varyfrom about one hour to ten hours or more. The reaction time is of coursedependent on temperature, the lower temperatures necessitating longerreaction times.

The steroid phosphate amine salt product maybe'precipitated byconcentration of the organic solvent, followed by cooling of theconcentrate'to about room temperature or lower. The product may then berecovered by conventional means such as filtration. -The otherconstituents of the reaction mixture remain in solution, so thatseparation of a product of high purity is effected.

i For the purpose of specific illustration the product ofprednis'olone-zl-dihydrogen phosphate triethylamine salt is given below.1'13, I'7a -dihydroxy-21-iodo-1,4-pregnadiene3,20 dione is reacted withexcess 'triethylamine and phosphoric acid, the molar rati'oof the lattertwo being about 2: 1, accordingto the following equation:

alkali metal salts thereof. The'conversion to the dihydrogen phosphateis most'readilyeffected by contact of a solution of the steroidphosphate amine salt in a suitable solvent such as methanol, witha"st1'on'gly acidic anion exchangeresinin its hydrogen form; :Amon'gtheisuitable anion "xchange're'sins are polystyrene resins'crosselinke'd "with divinylbenzene having the exchangeablei hydrog'enatoms in the formof'sulfonic acid groups. :Aneexample of such=a resin isAmberlite IR-.-.imade :by:Rohm and Haas Company, "Philadelphia. I Thez'resulting'steroid dihydrogen phosphate, which :is a=:21 dihydrogenephos- In the preferred mode of operation required.

This invention will now be further described with reier phate esterof a4-pregnene compound such, as cortisone or hydrocortisone or a1,4-pregnadiene such as prednisone ence to specific embodiments thereof.

' Example 1 A solution of 102 cc. of triethylamine and 24 cc. ofphosphoric acid in 144 cc. of acetonitrile was poured into a suspensionof 48 g. of 11B,l7a-dihydroxy-21-iodo-,

1,4-pregnadiene 3,20-dione and 6 g. of silver phosphate in 360 cc. ofacetonitrile. The mixture was boiled at reflux for about one andone-half hours with a clear solution resulting after about 20 minutes.The solution was.

filtered hot to remove trace insolubles and the filtrate concentratedunder reduced pressure at a bath temperature of 50 C. to a volume of 120cc. The concentrate was aged for 16 hours at 25 C. and the resultingslurry was diluted with 120 cc. of acetonitrile, aged at to C. for onehour and filtered. The filter cake of 1118,l7u,21-trihydroxy-1,4-pregnadiene-3,2O dione 21 phosphate triethylaminesalt (prednisolone 21-phosphate triethylamine salt) was washed withacetonitrile and ether and dried in air at 25. C. Yield 33.7 to 34.8 g.(61% to 63%); dec. 201 C.; E% 268 at 2,470 A. Analysis showed thetriethylamine content to be 19.2% (theoretical: 18.7%). Electrophoresisshowed a single spot.

A solution of 20 g. of 11,8,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione21 hydrogen phosphate triethylamine salt was dissolved in 100 cc. ofmethanol, and the solution passed over an anion exchange resin columncontaining 38.4 cc. of Amberlite IR-120 resin in its hydrogen form overa period'sof one and one-half hours. The column was eluted with 200 cc.of methanol. The eluate' showed a constant slight spot with anutraviolet scanner I when elution Wascomplete. The eluate wasneutralized by the addition of a solution of 1.6 g. of sodium hydroxidein l60,cc. of methanol. The neutralized solution had a pH of 5.7 asdetermined by pH indicator paper, or about 6.7 for a 50% aqueousmethanol solution as determined by a pH meter. The neutralized solutionwas concentrated under reduced pressure at a temperature below 35 C. toa volume of 140 cc; A precipitate of17;3,21-dihydroxy-4-pregnene-3,11,20-trione ZI-phosphate monosodium saltwas obtained by the slow addition of 600 cc. of absolute ether at 25 C.The product was filtered and Washed with ether and dried in air at 25 C.Yield 17.2 to 17.6 g. (95% to 97%); moisture (Karl Fischers method)5.5%; E% 312 to 314 at 2,470 A. Analysis revealed a trace (0.18%) oftriethylamine. Electrophoresis showed a single spot.

Example 2 obtained as in Example 1.

Example 3 To a slurry of 3.72 g. of 11/3,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-methanesulfonate in 30 cc. of acetonitrile wasadded a solution of 8.5 cc. of triethylamine and 2 cc. of 85% phosphoricacid in 12 cc. of acetonitrile. The mixture was boiled under reflux forthree hours, concentrated under reduced pressure to about cc., dilutedwith about 50 cc. of absolute ethanol, reconcentrated to about 10 cc.,and allowed to stand until crystallization was complete. with 8 cc. ofacetonitrile, filtered, and the product, 1119, l7u,2ltrihydroxy'l;4-pregnadiene-3,20 dione 21 phosphatetriethylamine salt,washed with ether. Yield 1.7 (37%); M.P. 200-201L5 C.E% 269 at 2,470 A.

The mixture was diluted Exlzhzple 4 To, a slurry of 4g. of1IBJ'IurdlhYtliI'OXY-ZI-iOdO-lpregnene-3,20-dione, 6.4 g. of silverphosphate and 3.2

1 g. of diatomaceous earth filter aid and 30 cc. of acetonitrile wasadded a solution of 8.4 cc. of triethylamine and 2 cc. of 85% phosphoricacid in 12 cc. of acetonitrile. The mixture was heated at 50 to 55 C.for seven hours, filtered, and the filtrate concentrated under re- 7duced pressure to about 10 cc. The residue was diluted with ca. 50 cc.of absolute ethanol, reconcentrated to about 10 cc., and allowed tostand until crystallization was complete. The mixture was diluted with 8cc. of acetonitrile, cooled, and washed with ether. The product obtainedwas 11p,l7a,21-trihydroxy-4-pregnane-3,20-dione 21-phosphatetriethylamine salt. Yield, 1.94 g. (42.4%); M.P. l83-187; E% 298 at2,470 A.

Example 5 To a slurry of 4 g. of 1113,17a-dihydroxy-21-iodo-4-pregnene-3,20 dione, 6.4 g. of silver phosphate, and 3.2 g. ofdiatomaceous earth filter aid in ml. of tertiary butyl alcohol was addeda slurry of 8.5 ml. of triethylamine and 2.0 ml. of 85% phosphoric acidin 22 ml. of tertiary butyl alcohol. The mixture was boiled under refluxfor three hours, filtered, and the filtrate concentrated under reducedpressure to about 10 ml. The residue was diluted with ca. 50* cc. ofabsolute ethanol, re-

concentrated to about 10 cc., and allowed to stand until crystallizationwas complete. The mixture was diluted ml. of acetonitrile.

with 7 ml. of acetonitrile and the product was washed with ether.Electrophoresis of the product gave one spot having the same mobility asa known sample of 115.17 21- trihydroxy-4-pregnene-3,20-dione21-phosphate triethylamine salt. M.P. 175-180 C.; E% 298 at 2,480 A.

I Example. 6

'f To a slurry of 4.0 g. of 11 3,l7a-dihydroxy-2l-iodo 4pregnene-3,20-dione'and 0.5 g. of silver phosphate and 22 ml. ofacetonitrilewas added a mixture of 14.36 ml. of tri-N-butylamine, 2.2ml. of phosphoric acid and 20 The mixture was boiled under reflux forthree hours, filtered, and the filtrate concentrated under reducedpressure to a small volume. The residue was triturated with absoluteethanol and filtered. The filtrate was concentrated under reducedpressure. The residue was identified as11,6,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione 21-phosphatetri-N-butylamine salt by electrophoresis.

Example 7 To a slurry of 4.0 of 17a-hydroxy-21-iodo-4-pregnene3,11,20-trione and 0.5 g. of silver phosphate and 30 ml. of acetonitrilewas added a solution of 8.5 ml. of triethylamine and 2.0 ml. of 85%phosphoric acid in 12 ml. of acetonitrile. The mixture was boiled underreflux for three hours, filtered, and thefiltrate concentrated underreduced pressure to a small volume. The residue was triturated withmethanol and filtered. -The filtrate was concentrated under reducedpressure to a small volume. The residue was identified as17a,21-dihydroxy-4-pregnene-3,l1,20-dione 21-phosphate triethylaminesalt by electrophoresis.

Example 8 To a slurry of 1.6 g. of 2l-chloro-11/8,17a-dihydroxy-1,4-pregnadiene-3,20-dione, 3.2 g. of silver phosphate, and 1.6 g. ofdiatomaceous earth filter aid in 11 ml. of acetonitrile was added asolution of 4.3 ml. of triethylamine and 1.0 ml. of 85 phosphoric acidin 10 ml. of acetonitrile. The mixture was boiled under reflux for sixhours, filtered, and the filtrate concentrated under reduced pressure toabout 5 ml. The resulting slurry was diluted with 5 ml. of acetonitrileand allowed to stand until crystallization was complete. The mixture wasfiltered and the product washed with .acetp itrile and ether. Theproduct was 1 1B,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione2l-phosphate triethylamine salt. Yield g73-g. (3127 "Mil:f1-9920 1 G1;E%'-279 at- 2,470 A.

diluted witln 8- cc..ofacetonitrile, cooled, and'the product:

washed with ether. The resulting; product was 115,17,- 21trihydroxy-4-pregnene-3,20+dione 21 phosphate triethylamine salt. Yield1.33 g, (29%); M.P. 184188 C.

Example 10 To a slurry. of- 233g. ofl118,17a,21-trihydroxy-4-pregnene-3,20-di one 2l-p-t0luenesulfonate in12 cc. of acetonitrile. was added a solution. of 4.2.cc.olf;triethylamine and Ice. of 85% phosphoric acid in'10 cc. ofacetonitrile. The solution that-resulted-was allowed: to" stand. at roomtemperature for six hours, boiled under reflux for one hour and"concentrated to. a syrup under reduced pressure. The syrup was allowedto stand for six days, during which time 11p,17u,21-trihydroxy-4-pregnene-3,20-dione-21-hydrogen. phosphatetriethylamine. salt crystallized. The slurry was diluted with 3.5. cc.of acetonitrile,.allowed to. stand24 hours at room tempcrature,.cooledalt-.0 to 5 C.' for one hour, filtered,and the product washedWithether.Yield ,;v 0158- g. (25 i Example: 11

The process of Example: 11is= carried out using17a-hydroxy-Zl-iodo-l,4-pregnadiene-3,11,20-dione. as the startingmaterial. The. product obtained .is 178:,21-dihyjdroxy-1,4-pregnadiene-3',1.1,20-4tribne 21-phosphate. triethyl amine salt.

V Example 12" -Theprocess' of'. Example. 5 is carried out using17ahydroxy-Zl-iodo-4-pregnene-3,11,20-trione as the starting material.The. productv 17,2l-dihydroxy-4epregnene-3, 11,20-trione 21-phosphatetriethylaminesalt is obtained.

The process of example 7 is'carried out using 90L-fl1101'0-11/3,17a-dihydroxy-21-iodor4-pregnene-3,ZO-dione as the startingmaterial. A residue of 9a-fl1l01'O-11B,17oc,2ltrlhydroxy- 4 pregnene--3,20-dione 21-phosphate. triethylamine salt is obtained.

Example 14 The processor Example 9 is carried outwith 115,170;-dihydroxy-21-iodo-2ot-methyl-4-pregnene3,20 dione as the startingmaterial. The product is 11B,l.7u,21-t-rihydroxy- 2-methylr4-pregnene-3,20-dione 2l.-phosphate triethylamine. salt. s

Example 15 solutionof bis-triethylaminezphosphate; was prepared byslowly adding 2.36 ml. of phosphoric acid to 20 nilifo'ffacetfoni'trilecontaining 9'.9 ml. of t'riethylamineat? 207 C: This; solution'was addedto a stirred mixture 4.70 of '9Ex-fiuoro-l1B;17,2ll-trihydroxy-loaamethyl nil-of acet'oriitiile'. The mixture washeated undeijre for four hoursand then evaporated under reducedpressuret'o avolu'm'eof 12 ml. Thismixturewas aconcentrated solutionof'9wflu0ro-l1}3,17a,21-trihydroxy-l6o= methyl-1,4-pregnadiene-3,20di0ne 2l-phosphate triethylamine salt with some inorganicphosphate.

The mixturew'as cooled, 25 m1. of methanol added, andftlie. cooledmixture treated with 33 ml. of 1.89 N methanolic sodium methoxidesolution. The precipitated inorganic phosphates were removed by suctionfiltration and washed thoroughly with methanol. The combinedfiltrateswere evaporated. under reduced pressure to a" volume of 12 ml. and:treated with 30 ml. of methanol. The resulting cloudy solution wasclarified by filtration through diatomaceous earth. The volume of thefiltrate was brought to 40 ml. by the addition of methanol, and ml;of'ether was added with stirring. The precipitated product, which was9a-fluoro-Bl1,17a,21-trihydroxy-16amethyl 1,4-pregnadiene-3,20-dione21-phosphatesodiumsalt, was collected by suction filtration, and washedwith acetone and then with ether. The weight of the air-dried? materialwas 306g.

Example 18 A solution ofbis-triethylamine.phosphatewas prepared byslowly adding 2.35 ml. or 85% phosphoric acid tov 14.3 mLor'.acetonitrile.containing 9.9 ml. of triethylamine atr20.="". Thissolution was added to a stirred mixture. of 5 g. of9a-fiuoro-1lp,17wdihydroxy-2l-iodo loemethyl-1,4-pregnadiene-3,20-dioneand 35 ml. of ace tonitrilc: The mixture was heated under reflux for sixhours and then evaporated under reduced pressure to a volume of 12 ml.This filtrate contained a concentrated solution of 9ufiuoro-1-l/3, 17a,2 l-trihydroxy-lfia-methyl- 1,4-pre'gnadiene-3,20-dione' 21-phosphatetriethylamine. salt (9a-fluoro-16u methylprednisolone 21-phosphate.triethylamine salt), together with inorganic phosphates.

The concentrated solution was cooled, 25 ml. of meth@ anolwas added, andthe cooled mixture treatedwith 33; ml. of 1.89 N methanolic sodiummethoxide. The precipitated inorganic phosphates were removed by suctionfiltration and washed thoroughly with methanol. The combined filtrateswere evaporated under. reduced. pres, sure to'ra volume of 12 m1.,treated with 27 ml. ofrnethanol and 5.00 mg. of decolorizing charcoal(fNuchar C 100.0 N) and clarified by suction filtration over a bed of.Cellite. The volume of the filtrate was. brought to 40 ml. 'by theaddition of methanol, and 120ml. of ether was a'ddedwith stirring. Theprecipitated product was collected by suction filtration and washed withacetone followed by ether, and air-dried.

Yield 3.81 g.

Example 19 A solution of bis-triethylamine phosphate was prepared byslowly adding 37.5 ml. of 85% phosphoric acidto 230 ml. of acetonitrilecontaining ml. of triethylamine. The solution was added to astirredmixture of 80 g. of 900- fluoro 11fl,l-7oc dihydroxy 21 iodo 16a methyl1,4 pregnadiene 3,20 dione, 939. g. of trisilver'phosphate, and 576 ml.of acetonitrile. The mix ture was'boiled' under reflux for six hoursandthen evaporated under reduced pressure to a volume ofml. After theaddition of 640 ml. of methanol, the silver-containingby-product wasremoved by suction filtration and washedwith methanol. The combinedfiltrates were evaporated under reduced pressure to a volume of 210'ml., affording a concentrated solution of 9a. 'fluoro 11p,17u,21trihydroxy 1,4 pregnadiene 3,20 dio'n'e 21-phosphate triethylamine salt.

The concentratedsolution-was diluted with 420 ml; of

aosas'ra diluted to 656 ml. by the addition of methanol, and 1600 m1. ofether was added with stirring. The precipitated product which was 9ozfluoro 113,17 dihydroxy 16a methyl 21 phosphoroyloxy 1,4 pregnadiene3,20 dione monosodium salt was collected by suction filtration andwashed first with acetone and then with ether, and air-dried. 7

Yield 56.7 g.

Example 20 The procedure of Example 17 is repeated, using 115,170:dihydroxy 21 iodo 3,20 pregnanedione as the starting material. Thecompound 11;3,l7u,21 trihydroxy 3,20 pregnanedione 21 phosphatetriethylamine salt is formed in solution and converted withoutpurification or recovery to the corresponding monosodium salt.

Example 21 The procedure of Example 17 is repeated, using 1l;3,l7ccdihydroxy 21 iodo 1604 methyl 3,20 pregnanedione as the startingmaterial. The compound 1lB,17u,21 trihydroxy 16oz methyl 3,20pregnancdione 21 phosphate triethylamine salt is formed in solution andconverted without purification or recovery to the correspondingmonosodium salt.

Example 22 The procedure of Example 17 is repeated, using 90: fluoro115,170: dihydroxy 21 iodo 16a methyl 3,20 pregnanedione as the startingmaterial. The compound 9a fluoro l1,8,17a,21 trihydroxy 16a methyl 3,20pregnanedione 21 phosphate triethylamine salt is formed in solution andconverted without purification or recovery to the correspondingmonosodium salt.

This application is a continuation-in-part of copending' application ofJohn M. Chemerda, Roger J. Tull, and James F. Fisher, Serial No.697,513, filed November 20, 1957, now abandoned.

What is claimed is:

1. A process for producing tertiary lower alkyl amine salts ofunsaturated pregnane-Zl-dihydrogen phosphate esters having a generalformula of the group consisting of and the therapeutically activenuclear substituted derivatjives thereof, where R; is selected from thegroup'cofi: sistingof Y X Q'." H

and o: and. R R man, are lower alkyl radicals, which comprises combininga compoundhavinga' general formula of the group consisting of CHuY C=O-orr R1 I CH and CHZY C=O --0H 1 CH:

where R; is as previously defined and Y is a radical se-' lected fromthe group consisting of halogens having an atomic weight of at least 35and lower hydrocarbon sulfonyloxy radicals of the formula -OSO R where Ris a hydrocarbon radical containing from one to 10 carbon atoms, with atertiary lower alkyl amine phosphate in an alkaline organic solventmedium.

2. The process of claim 1, wherein the tertiary lower alkyl amine istriethylarnine.

3. The process of claim 1, wherein the steroid starting material is a4-pregnene having the general formula CHzY where R; is selected from thegroup consisting of Ho Hz and O: and Y is a radical selected from thegroup consisting of chloro, bromo, iodo, methylsulfonyloxy, andp-tolylsulfonyloxy.

4. A process for preparing prednisolone-Zl-phosphate triethylamine salt,which comprises reacting11,8,l7a-dihydroxy-Zl-iodo-1,4-pregnadiene-3,20-dione with triethylaminephosphate in an alkaline organic solvent medium.

5. A process for preparing 9a-fluoro-l6oc-methyl-prednisolone-Zl-phosphate triethylamine salt, which comprises reacting9a-fluoro 11B,17u-dihydroxy-21-iodo-16a-methyl-1,4-pregnadiene-3,20-dione with triethylamine phosphate in an alkalineorganic solvent medium.

6. A process for preparing 2l-phosphate tertiary lower alkyl amine saltsof compounds selected from the group consisting of3,20-dioXo-llfi,l7tz,2l-trihydroxy and 3,11, 20-trioxo-17u,2l-dihydroxysteroids of the pregnane series, which comprises reacting acorresponding steroid selected from the group consisting of the3,20-dioxo-11fi, lower alkyl amine phosphate in an alkaline organic sob.I7cz-dihydroxy 2I-ha1o and 3,ILZO-trioxo-17a-hydrokyvem'medium. 21-ha1osteroids of the pregnane series wherein the halogen has an atomic weightof at least 35 and the 3,20- 7 References Cited i the of Ibis piateiifdioxo-11;8,17a,21-trihydroxy and 3,11,20-tIiOX0-17m,21- 6 UNITED STATESPATENTS dihydroxy 21-lower hydrocarbon. sulfonates-of the preg- 2779775I'Sarett, l

nane series whereinv the hydrocarbon sulfonate radical contains from oneto 10' carbon atoms, Withatettiary t '""V""'T

1. A PROCESS FOR PRODUCING TERTIARY LOWER ALKYL AMINE SALTS OFINSATURATED PREGNAME-21-DIHYDROGEN PHOSPHATE ESTERS HAVING A GENERALFORMULA OF THE GROUP CONSISTING OF